Our laboratory has developed the hypothesis that the generation of cytotoxic oxygen free radicals occupies an important role in the pathophysiology of ischemic/reperfusion injury. Our previous work has developed the working hypothesis that myocardial ischemia results in the intracellular production of free radicals and the "priming" of the ischemic myocyte for free radical production. Reperfusion, with the reintroduction of molecular oxygen would result in a "burst" of free radical production and the extension of ischemic injury (reperfusion injury). This hypothesis is supported by our observations that both in vitro and in vivo, enzymatic scavengers of oxygen free radicals protect myocardial hemodynamic, mechanical and sarcoplasmic reticulum function during the course of surgically induced, global hypothermic and normothermic ischemia followed by reperfusion. We propose to extend these concepts and using both the isolated, working rat heart model and our canine model of ischemia and reperfusion address the following specific aims with each study designed to answer two questions: What is the underlying mechanisms? and can this pathophysiologic cascade be interrupted? Specific aim #1 will address the concept of pretreatment in an attempt to elucidate the source of free radicals during ischemic/reperfusion injury and to demonstrate that pharmacological scavengers of free radicals (Coenzyme Q-10 and Alpha-tocopherol) or inhibitors of free radical generation (indomethacin and ibuprofen for the cyclooxygenase system and allopurinol for the xanthine oxidase system) will protect myocardial hemodynamic, mechanical, sarcolemmal and sarcoplasmic reticulum during the course of ischemic reperfusion injury. Specific aim #2 will extend this hypothesis to the concept of improved cardioplegic preservation during the ischemic period. We will hypothesize that these scavengers or inhibitors of oxygen free radical generation along with the anionic channel blockers DIDS and phenylglyoxal will interrupt the positive feedback mechanism of free radical generation to the extracellular space with progressive injury to adjacent myocardial cells. Specific aim #3 will then establish the new concept that posttreatment of the previously ischemic/reperfused mycardium using coronary sinus retroperfusion with the delivery of scavengers or inhibitors of oxygen free radicals which will further preserve and protect myocardial function. Using this combined "surgical and physiological" approach, these studies will result in new and applicable data to the problem of ischemic/reperfusion injury.